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lox-1

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Official Full Name
oxidized low density lipoprotein (lectin-like) receptor 1
Background
This gene encodes a low density lipoprotein receptor that belongs to the C-type lectin superfamily. This gene is regulated through the cyclic AMP signaling pathway. The encoded protein binds, internalizes and degrades oxidized low-density lipoprotein. This protein may be involved in the regulation of Fas-induced apoptosis. This protein may play a role as a scavenger receptor. Mutations of this gene have been associated with atherosclerosis, risk of myocardial infarction, and may modify the risk of Alzheimers disease. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Feb 2010]
Synonyms
OLR1; oxidized low density lipoprotein (lectin-like) receptor 1; LOX1; LOXIN; SLOX1; CLEC8A; SCARE1; oxidized low-density lipoprotein receptor 1; hLOX-1; ox LDL receptor 1; lectin-type oxidized LDL receptor 1; scavenger receptor class E, member 1; C-type lectin domain family 8 member A; oxidized low-density lipoprotein receptor 1, soluble form; oxidised low density lipoprotein (lectin like) receptor 1; LOX 1; LOX-1; Oldr1; Oldlr1

OLR1, a lectin-like scavenger receptor, is highly conserved in mammals and it is capable of recognizing several ligands including the protein moiety of oxidized-LDL (ox-LDL), advanced glycation end-products, gram-positive and gram-negative bacteria and apoptotic cells. OLR1 is primarily expressed in vascular cells and vasculature-rich organs, and its activation by a wide range of stimuli indicative of dyslipidemia, inflammation and damage initiates several signaling cascades including MAPKs, other protein kinases as well as transcription factors NF-kB and AP-1.

Overexpression of OLR1 has been shown in cellular components of atherosclerotic lesions. Deletion of Olr1 in Ldlr knockout (KO) mice results in much smaller atherosclerotic lesions associated with a drastic reduction of inflammation in the aortic wall. Olr1 abrogation also attenuates angiotensin II-induced hypertension. Similarly, abrogation of Olr1 reduces the extent of ischemia/reperfusion injury.

Atherosclerosis is an inflammatory vascular disease accompanying with the occlusion of the arterial vessels. The early atherosclerotic lesions include sub-endothelial accumulations of lipid-engorged macrophages (foam cells), which are represented as ‘fatty streak’. Fatty streaks are not clinically harmful, but they can be the precursors of more advanced fibrous and plaque-type lesions characterized by the accumulation of lipid-rich necrotic debris and vascular smooth muscle cells (VSMCs). Like other scavenger receptors implicated in the atherosclerosis, the OLR1 mediated the OxLDL-induced NF-κB activation in VSMCs, which in turn augmented the ICAM-dependent monocyte adhesion onto the activated VSMCs. More striking finding is that the depletion or internalization of the OLR1 impaired the activation of PDGFRβ, a major growth factor receptor of VSMCs. This evidence suggests a novel function of OLR1 as a potential co-receptor for PDGFRβ, similar to a co-receptor neuropilin-1 for vascular endothelial growth factor receptor-2. Thus, it is likely that OLR1 is the first scavenger receptor that simultaneously coordinates the growth signaling and the inflammatory response in VSMCs (Figure 1). If this is the case, it is suspected that a PDGFR-targeted therapy against atherosclerosis and in-stent restenosis may cause a medical complication in hypercholesterolemia or hyperlipidemia patients.

Figure 1. OLR1 plays a dual receptor function in VSMCs . An association between obesity and atherosclerotic disease states in humans is well established.

Associations with obesity have been found for various cancers, including breast and prostate neoplasms, suggesting a mechanistic overlap in the pathobiology of atherogenesis and tumorigenesis. Recently, Olr1, acting through NF-kB mediated inflammatory signaling, was strongly implicated in carcinogenesis. OLR1 locates within the area of chromosome 12p, which has been identified as the AD-susceptible region, and plays a role in lipid metabolism. Therefore, it has also been suggested to be a good candidate gene for Alzheimer’s disease (AD). Several SNPs within OLR1 have been reported to have association with AD among Caucasians.

References:

  1. Khaidakov M, et al. Oxidized LDL receptor 1 (OLR1) as a possible link between obesity, dyslipidemia and cancer. Plos One, 2011, 6(5):e20277.
  2. Kang D H, et al. Vascular Proteomics Reveal Novel Proteins Involved in SMC Phenotypic Change: OLR1 as a SMC Receptor Regulating Proliferation and Inflammatory Response. Plos One, 2015, 10(8):e0133845.
  3. Wang Z T, et al. Association of lectin-like oxidized low density lipoprotein receptor 1 (OLR1) polymorphisms with late-onset Alzheimer disease in Han Chinese. Ann Transl Med, 2018;6(10):172.
  4. Changping H, et al. LOX-1 abrogation reduces myocardial ischemia–reperfusion injury in mice. Journal of Molecular & Cellular Cardiology, 2008, 44(1):76.